Benzothiazole, substitution

Thiazoles react readily with alkyl halides to form the corresponding thiazolium salts. Many examples exist in the literature and studies of the effect of thiazole ring substituents upon the rate of reaction have been well reviewed < 1984CHEC(6)235>. Thiazoles and benzothiazoles substituted with a hydroxy, thio, or amino group can undergo alkylation equally at either the endo- or exocyclic heretoatom. This reactivity has been discussed elsewhere < 1996CHEC-II(3)373>. 

Chemical Properties of Benzothiazoles. - Substitution Reactions on the Thiazole Ring. 2-Chlorobenzothiazoles are obtained by substitution of... 

Thiadiazoles are weak bases. On quatemization, e.g. with dimethyl sulfate, mixtures of 2- and 3-methyl-1,2,3-thiadiazoles are formed. Electrophilic substitution of the C-atoms could not be achieved. With 1,2,3-benzothiazoles, substitution occurs on the benzene ring. For instance, with nitric acid the 4- and 7-nitro-l,2,3-benzothiadiazoles are obtained. Nucleophiles bring about ring-opening, e.g. ... 

The first mass spectrometric investigation of the thiazole ring was done by Clarke et al. (271). Shortly after, Cooks et al., in a study devoted to bicydic aromatic systems, demonstrated the influence of the benzo ring in benzothiazole (272). Since this time, many studies have been devoted to the influence of various types of substitution upon fragmentation schemes and rearrangements, in the case of alkylthiazoles by Buttery (273) arylthiazoles by Aune et al. (276), Rix et al. (277), Khnulnitskii et al. (278) functional derivatives by Salmona el al. (279) and Entenmann (280) and thiazoles isotopically labeled with deuterium and C by Bojesen et al. (113). More recently, Witzhum et al. have detected the presence of simple derivatives of thiazole in food aromas by mass spectrometry (281). 

After reaction for 15 min, the band near 3295 cm (not shown in Fig. 13) decreased significantly in intensity, indicating that the mono-substituted acetylene groups were reacting. New bands also appeared near 1539 and 1512 cm . After reaction for 30 min, several additional bands appeared near 1011, 1030, 1085, 1232, 1320, 1430, and 1515 cm. The bands near 1011, 1030, 1085, 1232, 1320, and 1430 cm were clearly related to the benzothiazole sulfenamide fragment of DCBS while the band near 1539 cm was related to zinc stearate. 

Heteroaromatic substituents can be incorporated onto the quinoxaline 1,4-dioxide ring system by condensing BFO with the appropriately substituted enamine, cyanomethyl, or 1,3-dicarbonylcompound. 2-Cyanomethyl-l,3-benzothiazole 27 reacted readily with BFO 1 in the presence of potassium carbonate to give the quinoxaline 1,4-dioxide 28 in good yield. 

Other advances in the use of IR spectroscopy are (1) The substitution of sulfur by selenium, for comparison with the spectra of benzimidazole-, benzoxazole-, and benzothiazole-2-thiones 72 (80AJC279). (2) The use of IR, as a quantitative tool to determine the association (homo- and heterodimers) of thia- and oxa-diazolin-5-thiones and -5-ones 73 (80NJC527). 

Similarly, for 2-(p-substituted-anilino)benzothiazoles (180 181), the relative proportions of the isomeric A -methyl derivatives produced on reaction with methyl iodide in neutral solution has been related to... 

Methylphenyl)benzothiazole (80IC762) and 2-benzylbenzothiazole (95ICA(239)125) can be cyclopalladated. In the latter case, cylopalladation occurs upon reaction with palladium(II) acetate and gives the product 80. With lithium chloride, sodium bromide, or sodium iodide, a series of three products of substitution of the acetate group 81 (X = C1, Br, I) results. Pyridine, 2- and 3-methylpyridine, 2,6- and 3,5-dimethylpyridine cause the transformation of the chelate complexes 81 (X = C1, Br, I) and formation of the mononuclear products 82 (R = z= R" = = R = H, X = Cl, Br, I ... 

It is therefore not unexpected to find a similar effect in a heterocycle fused to a benzene ring. Reaction of the substituted benzothiazole, 71, with sodium hypochlorite in a mixture of sodium hydroxide and ammonia affords the sulfenamide, 72, probably by the intermediacy of the sulfenyl chloride. 

Attempts to brominate benzothiazoles with bromine in acetic acid at room temperature have given only perbromides, but when these were heated in ethanolic solution, products in which bromine had substituted in the benzene moiety were detected. At 100°C bromine in acetic acid gave rise to the 4,6-dibromo derivative in accord with calculated -densities (70BSF2705). Vapor-phase bromination gave the 2-bromo product (84MI27). 

Most recent syntheses of fluorinated benzothiazoles make use of nucleophilic substitution. Potassium fluoride in acetonitrile converted 40 into the 2-fluoro derivative (R = 6-nitro) in 99% yield. When the solvent was dimethylformamide the 2-dimethylamino derivative was formed instead [80JCS(P1)2358], and similar behavior was reported earlier (77BSF171). 

Benzamidoselenazole, bromination, 243 2-Benzamidoselenazoles, hydrolysis to substituted selenoureas, 228 hydrolysis to 2-aminoselenazoles, 229 Benzothiazole, 30... 

Manganese(III)-promoted radical cyclization of arylthioformanilides and a-benzoylthio-formanilides is a recently described microwave-assisted example for the synthesis of 2-arylbenzothiazoles and 2-benzoylbenzothiazoles. In this study, manganese triacetate is introduced as a new reagent to replace potassium ferricyanide or bromide. The 2-substituted benzothiazoles are generated in 6 min at 110°C imder microwave irradiation (300 W) in a domestic oven with no real control of the temperature (reflux of acetic acid) (Scheme 15). Conventional heating (oil bath) of the reaction at 110 °C for 6 h gave similar yields [16]. 

Indolines, benzoxazole, and benzothiazole are possible as 2-methylene heterocycles. The number of known spirooxazine derivatives is much less than for the spiropyrans. This may be partly due to lack of many substituted o-nitrosonaphthols and partly due to lack of sufficient stability of spiro-oxazines. The structures of parent spirooxazines and the Xmax of their photomerocyanine forms are listed in Table 5. The Xmax of the colored forms of compounds 41-43 are not described in the literature. 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

A series of 2-arylbenzothiazoles 41 has been synthesized via microwave irradiation of 1 1 mixture of ortho-nm i noth iophenol s 39 and alkyl or aryl acylacetonitriles <06JHC1609>. This reaction appears to be more efficient than that of ort/20-aminothiophenols with (3-ketoesters to form substituted benzothiazoles reported previously <05H(65)2119>. 

Scheme 6.219 Synthesis of benzothiazoles [391, 392], thiazolobenzimidazoles [370], and heteroaryl-substituted thiazolidinones [370],...

Thiadiazolines and thiadiazolium salts can undergo a thermally promoted rearrangement to yield 2-guanidinoben-zothiazoles. Thus the thiadiazoline 42 when heated in ethanol at reflux affords the benzothiazole 43 (Equation 11). There is evidence to suggest that this could be an electrophilic aromatic substitution reaction but a free radical mechanism was also proposed <2003SC2053>. 

In CHEC-II(1996), a very similar acid-catalyzed conversion of 3,5-diamino-l,2,4-thiadiazolidines to 2-guanidino-benzothiazoles was reported, and this was described as an electrophilic aromatic substitution reaction <1996CHEC-II(4)307>. 

A novel homolytic substitution yielded 2-(tributylstannyl)benzothiazole [35]. Thus, 2-(alkylsulfonyl)benzothiazole 49 was allowed to react with 2 equivalents of tributyltin hydride in the presence of catalytic azobisisobutyronitrile (AIBN) in refluxing benzene, affording 2-(tributylstannyl)benzothiazole along with tributylstannylsulfinate 50. 

Equation 154) <1996CHE1035>, of substituted 2-aminobenzothiazoles leading to imidazo[2,l-A benzothiazoles... 

Compound 98 reacts with carbon disulfide in the presence of an alkali solution to give 3 -mercapto-l,2,4-triazolo[4, 5 l,5][l,2,4]triazolo[3,4-A]benzothiazole 247. Treatment of product 98 with urea at 200°C for 4h affords 3 -hydroxy-l,2,4-triazolo[4, 5 l,5]-l,2,4-triazolo[3,4-A benzothiazole 99 (Scheme 20). Finally, the addition of concentrated phosphoric acid in the presence of sodium nitrite to compound 98 produces 1,2,3,4-tetra-zolo[l, 5 l,5]-l,2,4-triazolo[3,4- ]benzothiazole 248, and refluxing substituted benzaldehydes in acetic acid provides an easy access to 3 -aryl-l,2,4-triazolo[4, 5 l,5]-l,2,4-triazolo[3,4-A benzothiazoles 249 (Scheme 20) (Table 50) <2005IJC(B)625>. 

Trying to prepare precursors for the synthesis of 3-substituted [l,2,4]triazolo[5,l- ]benzothiazoles, 2-hydrazino-4-methylbenzothiazole 393 was submitted to reaction with formic acid, urea, carbon disulfide, and acetic anhydride to give compounds 230, 238, 89, and 394 (Scheme 45) <1998IJC(B)921>. 

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